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J. Biol. Chem., Vol. 283, Issue 27, 18743-18752, July 4, 2008

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Mechanisms Mediating the Enhanced Gene Transcription of P2X₃ Receptor by Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons^*

Manuela Simonetti, Rashid Giniatullin, and Elsa Fabbretti¹

From the Neurobiology Sector and Italian Institute of Technology Unit, International School for Advanced Studies (SISSA), 34014 Trieste, Italy and A. I. Virtanen Institute, University of Kuopio, Neulaniementie 2, FIN-70211 Kuopio, Finland

The molecular mechanisms underlying migraine pain remain unclear and probably require sustained facilitation in pain-sensing P2X₃ receptors gated by extracellular ATP in nociceptive sensory neurons. The major migraine mediator calcitonin generelated peptide (CGRP) is known to sensitize P2X₃ receptors to increase impulse flow to brainstem trigeminal nuclei. This process is mediated via changes in the expression and function of P2X₃ receptors initially through enhanced trafficking and, later, perhaps through augmented synthesis of P2X₃ receptors. To clarify the mechanisms responsible for CGRP-evoked long lasting alterations in P2X₃ receptors, we used as a model mouse trigeminal ganglion neurons in culture. CGRP activated Ca²⁺-calmodulin-dependent kinase II, which became localized to the perimembrane region and neuronal processes, a phenomenon already apparent after 30 min and accompanied by a parallel increase in cAMP-response element-binding protein (CREB) phosphorylation and nuclear translocation. These effects triggered increased P2X₃ receptor transcription and were prevented by expressing a dominant negative form of CREB. Increased P2X₃ receptor synthesis was partly mediated by endogenous brain-derived neurotrophic factor (BDNF) because of its block by anti-BDNF antibodies and mimicry by exogenous BDNF. Immunocytochemistry experiments indicated distinct subpopulations of BDNF- or CGRP-sensitive trigeminal neurons with only partial overlap. The present data indicate a novel mechanism for enhancing P2X₃ receptor expression and function in trigeminal sensory neurons by CGRP via CREB phosphorylation. BDNF was an intermediate to extend the sensitizing effect of CGRP also to CGRP-insensitive neurons. This combinatorial action could serve as a powerful process to amplify and prolong pain mediated by P2X₃ receptors.

Received for publication, January 11, 2008 , and in revised form, April 17, 2008.

^* This work was supported by Telethon Foundation Grant GGP 07032, the Italian Institute of Technology, and Fondo per gli investimenti della ricerca di base (to Prof. A. Nistri). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

¹ To whom correspondence should be addressed: SISSA, v. Beirut 2-4, 34014 Trieste, Italy. Fax: 39-040-3756502; E-mail: fabbre{at}sissa.it.

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